Method of isomerizing basically substituted stereoisomeric thioxanthenes



United States Patent C) ri`his invention relates to novel chemicalprocesses, and especially to novel processes for isomerization ofcertain geometrically asymmetric chemical compounds, said compoundsbeing subjected to isomerization either as a single stereoisorneric formor in the form of stereoisorneric mixtures containing an excess of onestereoisomer.

More particularly, the invention relates to processes which compriseheating geometrically asymmetric 9- (basicallysubstituted-alkylidene)-thioxanthenes in the presence of a stronglybasic agent.

The compounds referred to above, i.e. Q-(basically substituted-aliylidene) -thioxanthenes, including geometricab ly asymmetric speciesthereof, are known in the prior art; being described, for example, inGerman Federal Republic Auslegeschrift 1,944,163 of November 20, 1958.in the case ot geometrical asymmetric compounds of this class, onestereoisorner may be preferred, eg. because of greater economic value:for instance, as a medicinal agent. Thus, transZchioro-9o-dimethylamino-propylidene thioxanthene [M P. 98 C., MB. of thehydrochloride 225 (con.)], is a valuable medicinal agent, being used asa tranquilizer and antiemetic agent, whereas the c-orresponding cisisomer (Ml). 44 C., Mi. or" the hydro chloride 209 C.) is not useful forthese indications. When an excess inventory of an undesired isomer (eg,in the oase discussed above: the cis isomer) accumulates, it may bedesirable to subject said excess isomer to a process whereby it isconverted to the more desired steric form (eg, in the case discussedabove: the trans form). According to the present invention, theconversion is accomplished by heating the undesired isomer (either asthe single stereoisomer or in ladmixture with a lesser proportion of theother stereoisorner) with a strongly basic agent. r'he product of thisconversion process is an isomeric mixture containing the twoetereoisomers in approximateiy equal proportions. Tue more desiredsteric form can be separated from said mixture, andthe residual lessdesired stereoisomer can then again be subjected to the conversionprocess of the invention.

The invention cornprehends broadly the use of strongly basicisomerization agents, such as alkali metal hydroxides (particularlysodium hydroxide and potassium hydroxide), alkali metal lower alkoxides(particularly sodiumand potassium methoxides and ethoxides), alkalineearth metal hydroxides (eg. calcium hydroxide, barium hydroxide),alkaline earth metal lower alltoxides (eg. calciumand barium methoxidesand-etlioxides), alkali metal amides and alkaline earth metal amid-.es(eg. sodium arnide land calcium amide, in dimethylforrnamide), However,it is preferred to use a itali metal hydroxides and alkali metal lower`allcoxides, particularly those specifically referred to above.

Similarly, the invention is applicable broadly to any geometricallyasymmetric 9-(basically substituted)thi oxanthene. However, it isespecially applicable to such asymmetric compounds wherein thear-nuclear substituents are selected :from the group consisting oialkyl, aralltyl, ar/l, alltoxy, iarallroxy, aryloxy, alliylthio,aralltylthio, arylthio, halo, acyl, amino, hydroxyl and carboxyl. ln anespecially preferred embodiment, the processes of the invention areapplied to the isomerization of a geometrici-illy asymmetric compoundrepresented by the general formula o HC tri-C UTY H /C l i \s Yrepresents a basic substituent selected from the group consisting ofdi(lower ali;yl)amino, l-piperidyl, 4-rnorpholyl, l-piperazyl andl-hydroxyethyl-4-piperazylg X represents an rar-nuclear substituentselected from the group consisting of halogen, lower alkyl and lowerallioxy; and n represents a small integer from 1 to 2, inclusive.

(D wherein lo order to avoid splitting oit the basic substituent in the9-siide chain (eg, in the compounds of above Formula l: the substituentY), and also in order to avoid resinication of the resultingdecomposition product, it has been found advisable to conduct theisomerization reaction in an inert organic polar solvent, and in thepresence of an organic base corresponding to the basic substit-uent inthe 9-side chain (eg, in the case of a starting naterial under Formula labove: ian organic base Y-H, y serein Y represents the saine substituentas in said starting material). Any inert organic polar solvent can be`-n'iployeCL eg. lower aihanois, dirnethylformamide, and the like; butit is preferred to employ methanol or ethanol wnen working with analkali hydroxide or an alkali methoxide or ethoxide as the stronglybasic agent; and to empioy dirnethyliorrnamide when using an alkaliamide as the strongly basic agent. The organic base, eg., Y-H referredto above, is ordinarily employed in an amount of from about five toabout ten molar proportions with reference to the material to beisomerized. inasmuch as too gentle heating results in very long reactionperiods, whereas heating at very high temperatures results indiscoloration of the reaction mixture, it is preferred to conduct theheating at temperatures between about 513 C. and about 23" C.; and stillmore preferably, at temperatures between about 60 C. and about 180 C.

rthe invenfi disclosed in the `following examples, 't iitative thereof.Temperatures a ate; in degrees centigrade.

urample l 3 of cis2chloro-9-(esdiinethyiar 1o-propyiidene)- thioxai nencof MP. 1li a solution oi 0.5 g. of sodium in Z mi. ot methanol; and 5inl. of di ethylainine are heated in a tube for 12 hours at 6G". Thesolvent is d en oit, the residue is taken up in 30 to 40 rnl. o etier,the ether is washed free of alkali with water and then, after dryingover a iittie sodium sulfate, the ether is driven The syrupy residuecontains 1.4 to 1.5 of trans2cliloro9-(w-dirnethyiamino-propylidene)thioxanthe e together with 1.5 g. of the cis isomer. ln order to isolatethe readily crystaable trans isomer, syrupy residue is diluted vt'ith4.3 inl. oi petroleum ether of boiling range 1l8, and the mixture isallowed to stand in the refrigerator for 3 to i days. Uponrecrystarlization of the crude crystais from 1.5 to 2 ml. of methanol,there is obtained 0.75 g. of trans-2-chloro-9- (tu-dirne'ayiamino-propylidene)-thioxanthene of Ml. 93.

Example 2 4 g. or" a mixture of the cis and trans isomers of 2- ehloro a(wdimethylamino-propylidene)-thioxanthene (containing 20% of tre-.nsisomer, the remainder being the cis isomer) is heated in a sealed tubeat for 5 hours, in the presence of (M5 g. ot sodium hydroxide,

6 ml. of dirnethylamine and 25 ml. of methanol. Upon evaporation of thesolvent ythere is `obtained a syrupy residue which contains 42% of thetrans isomer (as determined by infrared analysis). The syrupy materialis worked up according to the indications in Example 1 in order toisolate crystallinetrans-2-chloro-9-(oJ-dimethylamino-propylidene)thioxanthene We claim:

1. A process for the isomerization of a geometrically asymmetriccompound of the formula wherein Y represents a basic substituentselected from the group consisting of di(lower alkyDaniino, 1-piperidyl,4- morpholyl, l-piperazyl and 1-hydroxyethyl-4-piper azyl;

X represents an 1r-nuclear substituent selected from the groupconsisting of halogen, lower alkyl and lower alkoxy; and

n is an integer selected from the group consisting of 1 and 2,inclusive;

which comprises heating at temperatures between about 50 C. and about200 C. said compound, in solution in a solvent selected from the groupconsisting of lower aikanol and dimethylformamide, in the presence of anagent selected from the group consisting of alkali metal hydroxides,alkali metal lower alkoxides, alkaline earth metal hydroxides, alkalineearth metal lower alkoxides, alkali metal arnides and alkaline earthmetal alnides and of an organic base of the formula Y--H, wherein Y isthe same substituent as in said compound.

2. A process lfor the isomerization of material selected from the groupconsisting ofthe cis and the trans isomers of 2-chloro 9(w-dimethylarnino-propylidene) thioxanthene and mixtures thereofcontaining the one isomer in excess over the other which comprisesheating said material, in solution in a lower alkanol, and in thepresence of dimethylarnine and an alkali metal-containing strong base,at a temperature between about C. and about 00n C.

3. A process according to claim 2 :wherein said strong base is sodiumhydroxide.

4. A process according to claim 3 wherein the temperature is betweenabout C. and about 180 C.

5. A process according to claim 2 wherein said strong base is sodiumlower alkoxide.

6. A process according to claim 5 wherein the ternperature is betweenabout 60 C. and about 180 C.

References Cited in the file of this patent UNITED STATES PATENTS2,951,082 Sprague et al Aug. 30, 1960 2,957,880 Rometsch Oct. 25, 1960FOREIGN PATENTS 1,044,103 Germany Nov. 20, 1958 OTHER REFERENCES Noller:Chemistry of Organic Compounds, 2nd edition, pages 354 to 357, W. B.Saunders Company, Philadelphia, 1957.

"Fieser et al.: Organic Chemistry, 3rd edition, pages 278 to 287, D. C.Heath and Co., third printing, 1958.

1. A PROCESS FOR THE ISOMERIZATION OF A GEOMETRICALLY ASYMMETRICCOMPOUND OF THE FORMULA
 2. A PROCESS FOR THE ISOMERIZATIN OF MATERIALSELECTED FROM THE GROUP CONSISTING OF THE CIS AND THE TRANS ISOMERS OF2-CHLORO - 9 - (W-DIMETHYLAMINO-PROPYLIDENE) - THIOXANTHENE AND MIXTURESTHEREOF CONTAINIGN THE ONE IOSOMER IN EXCESS OVER THE OTHER WHICHCOMPRISES HEATING SAID MATERIAL IN SOLUTION IN A LOWER ALKANOL, AND INTHE PRESENCE OF DIMETHYLAMINE AND AN ALKALI METAL-CONTAINING STRONGBASE, AT A TEMPERATURE BETWEEN ABOUT 50*C. AND ABOUT 200*C.